Label: BEPOTASTINE BESILATE solution/ drops
- NDC Code(s): 0378-7055-35, 0378-7055-67
- Packager: Mylan Pharmaceuticals Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
Drug Label Information
Updated March 20, 2018
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BEPOTASTINE BESILATE OPHTHALMIC SOLUTION safely and effectively. See full prescribing information for BEPOTASTINE BESILATE OPHTHALMIC SOLUTION.
BEPOTASTINE BESILATE ophthalmic solution, for topical application in the eye
Initial U.S. Approval: 2009INDICATIONS AND USAGE
Bepotastine besilate ophthalmic solution is a histamine H1 receptor antagonist indicated for the treatment of itching associated with allergic conjunctivitis. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Ophthalmic solution containing bepotastine besilate, 15 mg/mL (1.5%). (3)
CONTRAINDICATIONS
Hypersensitivity to any component of this product. (4)
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
The most common adverse reaction occurring in approximately 25% of patients was a mild taste following instillation. Other adverse reactions which occurred in 2-5% of subjects were eye irritation, headache, and nasopharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 3/2018
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Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Contamination of Tip and Solution
5.2 Contact Lens Wear
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
- *
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
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4 CONTRAINDICATIONS
Bepotastine besilate ophthalmic solution is contraindicated in patients with a history of hypersensitivity reactions to bepotastine or any of the other ingredients [see Adverse Reactions (6.2)].
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5 WARNINGS AND PRECAUTIONS
5.1 Contamination of Tip and Solution
To minimize contaminating the dropper tip and solution, advise the patient not to touch the eyelids or surrounding areas with the dropper tip of the bottle and to keep the bottle tightly closed when not in use.
5.2 Contact Lens Wear
Bepotastine besilate ophthalmic solution should not be used to treat contact lens-related irritation.
Bepotastine besilate ophthalmic solution should not be instilled while wearing contact lenses. Patient should remove contact lenses prior to instillation of bepotastine besilate ophthalmic solution, because benzalkonium chloride may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of bepotastine besilate ophthalmic solution.
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6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common reported adverse reaction occurring in approximately 25% of subjects was a mild taste following instillation. Other adverse reactions occurring in 2-5% of subjects were eye irritation, headache, and nasopharyngitis.
6.2 Post-Marketing Experience
Hypersensitivity reactions have been reported rarely during the post-marketing use of bepotastine besilate ophthalmic solution. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The hypersensitivity reactions may include itching, body rash, and swelling of lips, tongue and/or throat.
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no available human data for the use of bepotastine besilate ophthalmic solution during pregnancy to inform any drug-associated risks.
Oral administration of bepotastine besilate to pregnant rats or rabbits during organogenesis or during the pre/postnatal period did not produce adverse embryofetal or offspring effects at clinically relevant systemic exposures. Maternal toxicity was observed in the rabbits at the lowest dose administered, 20 mg/kg/day (215 times the maximum recommended human ophthalmic dose, RHOD, on a mg/m2 basis) [see Data].
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.
Data
Animal Data
In embryofetal development studies, oral administration of bepotastine besilate to pregnant rabbits throughout organogenesis did not produce teratogenic effects at maternal doses up to 500 mg/kg/day (approximately 5400 times the maximum RHOD, on a mg/m2 basis). A maternal no observed adverse effect level (NOAEL) was not identified in this study due to spontaneous abortion observed at the lowest dose tested, 20 mg/kg/day (approximately 215 times higher than the maximum RHOD, on a mg/m2 basis). Oral administration of bepotastine besilate to pregnant rats throughout organogenesis produced skeletal anomalies at 1000 mg/kg/day (5400 times higher than the maximum RHOD, on a mg/m2 basis), a dose that also produced maternal toxicity and lethality. No teratogenic effects were observed in rats at maternal doses up to 200 mg/kg/day (corresponding to an estimated blood plasma concentration 3300 times higher than that anticipated in humans at the maximum RHOD). A maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on a mg/m2 basis). Following a single 3 mg/kg oral dose in rats (16 times higher than the maximum RHOD, on a mg/m2 basis), the concentration of radio-labeled bepotastine besilate was similar in fetal liver and maternal blood plasma. The concentration in other fetal tissues was one-third to one-tenth the concentration in maternal blood plasma.
In a pre/postnatal development study, oral administration of bepotastine besilate to rats during the perinatal and lactation periods produced an increase in stillbirths and decreased growth and development in offspring at a maternal dose of 1000 mg/kg/day (5400 times higher than the maximum RHOD, on a mg/m2 basis). There were no observed adverse effects on offspring of rats treated with 100 mg/kg/day (540 times higher than the maximum RHOD, on a mg/m2 basis). Effects on parturition and maternal lethality were observed at 100 mg/kg/day and 1000 mg/kg/day, respectively. A maternal NOAEL was observed at 10 mg/kg/day (54 times higher than the maximum RHOD, on a mg/m2 basis).
8.2 Lactation
Risk Summary
There are no data on the presence of bepotastine besilate in human milk, the effects on the breastfed infant or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for bepotastine besilate ophthalmic solution, and any potential adverse effects on the breastfed infant from bepotastine besilate ophthalmic solution.
Animal Data
Following a single 3 mg/kg oral dose (16 times the maximum RHOD, on a mg/m2 basis) of radiolabeled bepotastine besilate to nursing rats 11 days after delivery, the maximum concentration of radioactivity in milk was 0.40 mcg-eq/mL 1 hour after administration; at 48 hours after administration, the radioactivity concentration was below detection limits. The milk radioactivity concentration was higher than the maternal blood plasma radioactivity concentration at each time of measurement. It is not known whether bepotastine besilate would be present in maternal milk following topical ocular administration.
8.4 Pediatric Use
Safety and efficacy of bepotastine besilate ophthalmic solution, 1.5% have not been established in pediatric patients under 2 years of age. Efficacy in pediatric patients under 10 years of age was extrapolated from clinical trials conducted in pediatric patients greater than 10 years of age and from adults.
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11 DESCRIPTION
Bepotastine besilate ophthalmic solution, 1.5% is a sterile, topically administered drug for ophthalmic use. Each mL of bepotastine besilate ophthalmic solution contains 15 mg bepotastine besilate.
Bepotastine besilate is designated chemically as 4-[(S)-(4-Chlorophenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid, benzenesulfonate salt. The chemical structure for bepotastine besilate is:
Bepotastine besilate is a white or creamish white crystalline powder. The molecular weight of bepotastine besilate is 547.06 daltons. Bepotastine besilate ophthalmic solution is supplied as a sterile, aqueous 1.5% solution, with a pH of 6.8.
The osmolality of bepotastine besilate ophthalmic solution, 1.5% is approximately 290 mOsm/kg.
Each mL of bepotastine besilate ophthalmic solution, 1.5% contains:
- •
- Active: bepotastine besilate 15 mg (equivalent to 10.7 mg bepotastine)
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- Preservative: benzalkonium chloride 0.005%
- •
- Inactives: monobasic sodium phosphate dihydrate, sodium chloride, sodium hydroxide to adjust pH, and water for injection.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bepotastine is a topically active, direct H1-receptor antagonist and an inhibitor of the release of histamine from mast cells.
12.3 Pharmacokinetics
Absorption
The extent of systemic exposure to bepotastine following topical ophthalmic administration of bepotastine besilate 1% and 1.5% ophthalmic solutions was evaluated in 12 healthy adults. Following one drop of 1% or 1.5% bepotastine besilate ophthalmic solution to both eyes four times daily (QID) for 7 days, bepotastine plasma concentrations peaked at approximately 1 to 2 hours post-instillation. Maximum plasma concentrations for the 1% and 1.5% strengths were 5.1 ± 2.5 ng/mL and 7.3 ± 1.9 ng/mL, respectively. Plasma concentrations at 24 hours post-instillation were below the quantifiable limit (2 ng/mL) in 11/12 subjects in the two dose groups.
Distribution
The extent of protein binding of bepotastine is approximately 55% and independent of bepotastine concentration.
Metabolism
In vitro metabolism studies with human liver microsomes demonstrated that bepotastine is minimally metabolized by CYP450 isozymes.
In vitro studies demonstrated that bepotastine besilate does not inhibit the metabolism of various cytochrome P450 substrates via inhibition of CYP3A4, CYP2C9 and CYP2C19. The effect of bepotastine besilate on the metabolism of substrates of CYP1A2, CYP2C8 and CYP2D6 was not studied. Bepotastine besilate has a low potential for drug interaction via inhibition of CYP3A4, CYP2C9 and CYP2C19.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term dietary studies in mice and rats were conducted to evaluate the carcinogenic potential of bepotastine besilate. Bepotastine besilate did not significantly induce neoplasms in mice receiving a nominal dose of up to 200 mg/kg/day for 21 months, or rats receiving a nominal dose of up to 97 mg/kg/day for 24 months. These dose levels correspond to systemic exposures approximately 350 and 200 times higher than that achieved at the RHOD, respectively.
The no observable adverse effect level for bepotastine besilate based on nominal dose levels in carcinogenicity tests were 18.7 to 19.9 mg/kg/day in mice and 9.6 to 9.8 mg/kg/day in rats (corresponding to systemic exposures approximately 60 and 20 times higher than that anticipated in humans at RHOD, respectively).
Mutagenesis
There was no evidence of genotoxicity in the Ames test (mutagenicity), in CHO cells (chromosome aberration), in mouse hepatocytes (unscheduled DNA synthesis), or in the mouse micronucleus test.
Impairment of Fertility
Oral administration of bepotastine to male and female rats at doses up to 1000 mg/kg/day (5400 times higher than the maximum RHOD, on a mg/m2 basis) resulted in reduction in fertility index and surviving fetuses. Oral administration of bepotastine besilate produced no observed adverse effects on fertility or reproduction in rats at oral doses up to 200 mg/kg/day (corresponding to an estimated blood plasma concentration 3300 times higher than that anticipated in humans at the RHOD).
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14 CLINICAL STUDIES
Clinical efficacy was evaluated in two conjunctival allergen challenge (CAC) studies (237 patients). Bepotastine besilate ophthalmic solution, 1.5% was more effective than its vehicle for relieving ocular itching induced by an ocular allergen challenge, both at a CAC 15 minutes post-dosing and a CAC 8 hours post-dosing of bepotastine besilate ophthalmic solution.
The safety of bepotastine besilate ophthalmic solution was evaluated in a randomized clinical study of 861 subjects over a period of 6 weeks.
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16 HOW SUPPLIED/STORAGE AND HANDLING
Bepotastine Besilate Ophthalmic Solution, 1.5% is a sterile, clear colorless to pale yellow solution practically free from particles. Each mL of bepotastine besilate ophthalmic solution contains 15 mg bepotastine besilate equivalent to 10.7 mg bepotastine.
Bepotastine besilate ophthalmic solution, 1.5% is supplied as a 5 mL or 10 mL solution in a 5 mL or 10 mL three piece container, respectively, each consisting of a white opaque low density polyethylene container with a white opaque open nozzle and a white high density polyethylene cap.
5 mL fill
NDC 0378-7055-35
carton of one bottle10 mL fill
NDC 0378-7055-67
carton of one bottleStore at 15° to 25°C (59° to 77°F).
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17 PATIENT COUNSELING INFORMATION
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- Sterility of Dropper Tip: Advise patients not to touch the dropper tip to any surface, as this may contaminate the solution and to keep the bottle tightly closed when not in use.
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- Concomitant Use of Contact Lenses: Advise patients not to wear contact lens if their eye is red and that bepotastine besilate ophthalmic solution should not be used to treat contact lens-related irritation. Patients should also be advised to remove contact lenses prior to instillation of bepotastine besilate ophthalmic solution, which may be reinserted after 10 minutes following administration.
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INSTRUCTIONS FOR USE:
Before you use Bepotastine Besilate Ophthalmic Solution, 1.5% for the first time:
- 1.
- Check to make sure that the tamper evident ring between the bottle and the cap is not broken (See Figure A). If the tamper evident ring is broken or missing, contact your pharmacist.
- 2.
- Tear off the tamper evident ring (See Figure B).
- 3.
- To open the bottle, remove the cap by turning it in the counterclockwise direction (See Figure C).
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.Manufactured by:
Micro Labs Limited
Bangalore – 560 099, INDIA
M.L. No.: KTK/28/357/2006
Revised: 3/2018
MCR:BEPO:R4 -
PRINCIPAL DISPLAY PANEL – 1.5%
NDC 0378-7055-35
Bepotastine
Besilate
Ophthalmic
Solution
1.5%For Topical Application
in the Eye.Rx only 5 mL
Each mL contains:
Active: bepotastine besilate
15 mg equivalent to 10.7 mg
bepotastine.Preservative: benzalkonium
chloride 0.005%Inactives: monobasic
sodium phosphate dihydrate,
sodium chloride, sodium
hydroxide to adjust pH, and
water for injection.Usual Dosage: Instill one
drop into the affected eye(s)
twice a day. See accompanying
prescribing
information.This product is sterile when
manufactured and should be
dispensed in the original
unopened container. Instruct
patient on precautions to
avoid contamination.Keep this and all medication
out of the reach of children.Store at 15° to 25°C
(59° to 77°F).Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.Made in India
MCR:705535:1C:R1
Mylan.com
M.L. No.: KTK/28/357/2006
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INGREDIENTS AND APPEARANCE
BEPOTASTINE BESILATE
bepotastine besilate solution/ dropsProduct Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0378-7055 Route of Administration OPHTHALMIC Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BEPOTASTINE BESILATE (UNII: 6W18MO1QR3) (BEPOTASTINE - UNII:HYD2U48IAS) BEPOTASTINE BESILATE 15 mg in 1 mL Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7) SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE (UNII: 5QWK665956) SODIUM CHLORIDE (UNII: 451W47IQ8X) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R) Product Characteristics Color YELLOW (clear colorless to pale yellow) Score Shape Size Flavor Imprint Code Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0378-7055-35 1 in 1 CARTON 05/28/2021 1 5 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product 2 NDC:0378-7055-67 1 in 1 CARTON 05/28/2021 2 10 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA206220 05/28/2021 Labeler - Mylan Pharmaceuticals Inc. (059295980)
